Process for preparing isoxaflutole

ABSTRACT

A process for preparing isoxaflutole of formula (I) wherein the process comprises: admixing (5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanone of formula (II) with acetic acid and hydrogen peroxide in the presence of a strong acid.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Ser. No.15/029,063, filed Apr. 13, 2016, which is a national stage applicationof PCT/IL2014/050898, filed Oct. 13, 2014, which claims priority to U.S.Provisional Application 61/891,464, Oct. 16, 2013, all of which arehereby incorporated by reference in their entirety.

BACKGROUND OF THE PRESENT SUBJECT MATTER

Isoxaflutole, known by the chemical name5-cyclopropyl-4-[2-methylsulfonyl-4-(trifluoromethyl)benzoyl]isoxazole,is represented by the following structural formula I:

Isoxaflutole is a p-hydroxyphenyl pyruvate dioxygenase inhibitor. Thisenzyme converts p-hydroxyphenyl pyruvate to homogentisate, a key step inplastoquinone biosynthesis. Inhibition of this enzyme leads to indirectinhibition of carotenoid biosynthesis, giving rise to chlorosis of newgrowth.

Isoxaflutole was first reported by B. M. Luscombe et al. (Proc. Br. CropProt. Conf.-Weeds, 1995, 1, 35).

The oxidation of(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) to isoxaflutole of formula (I) by reaction withchloroperbenzoic acid is disclosed both in US patent applications Nos.2005288516 and 2003055292. Such synthesis method has disadvantages bothin term of yield and cost and, therefore, is not applicable for largescale production.

The oxidation of sulphenyl phenyl-substituted isoxazoles derivativesgenerally according to U.S. Pat. No. 5,747,424 is conducted usinghydrogen peroxide, acetic anhydride and acetic acid or chloroperbenzoicacid in dichloromethane. However, no specific example for producingisoxaflutole is disclosed.

It would be highly desirable to have an improved process for theproduction of isoxaflutole which is suitable for industrial use, highlyefficient, low-cost, environmentally friendly, and provides a high yieldin a short reaction time, thereby overcoming the deficiencies of theprior art. The present subject matter provides such a process.

SUMMARY OF THE PRESENT SUBJECT MATTER

The present subject matter provides a process for preparing isoxaflutoleof formula (I) wherein the process comprises: admixing(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) with acetic acid, acetic anhydride, and hydrogenperoxide in the presence of a strong acid. In addition, the presentsubject matter provides a process for preparing isoxaflutole of formula(I) wherein the process comprises: admixing(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) with acetic acid and hydrogen peroxide in the presenceof a strong acid.

DETAILED DESCRIPTION OF THE PRESENT SUBJECT MATTER Definitions

Prior to setting forth the present subject matter in detail, it may behelpful to provide definitions of certain terms to be used herein.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this subject matter pertains.

As used herein, the term “mixture” or “combination” refers, but is notlimited to, a combination in any physical form, e.g., blend, solution,alloy, or the like.

The term “a” or “an” as used herein includes the singular and theplural, unless specifically stated otherwise. Therefore, the terms “a,”“an,” or “at least one” can be used interchangeably in this application.

Throughout the application, descriptions of various embodiments use theterm “comprising”; however, it will be understood by one of skill in theart, that in some specific instances, an embodiment can alternatively bedescribed using the language “consisting essentially of” or “consistingof.”

For purposes of better understanding the present teachings and in no waylimiting the scope of the teachings, unless otherwise indicated, allnumbers expressing quantities, percentages, or proportions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, each numerical parametershould at least be construed in light of the number of reportedsignificant digits and by applying ordinary rounding techniques. In thisregard, used of the term “about” herein specifically includes ±10% fromthe indicated values in the range. In addition, the endpoints of allranges directed to the same component or property herein are inclusiveof the endpoints, are independently combinable, and include allintermediate points and ranges.

The compound “(IIa)” refers to the reaction intermediate describedbelow:

Process for Preparing Isoxaflutole

The present subject matter provides a process for preparing isoxaflutoleof formula (I)

wherein the process comprises: admixing the compound of formula (II)

with acetic acid, acetic anhydride, and hydrogen peroxide in thepresence of a strong acid.

In another embodiment the present subject matter provides a process forpreparing isoxaflutole of formula (I)

wherein the process comprises: admixing the compound of formula (II)

with acetic acid and hydrogen peroxide in the presence of a strong acid.

In another embodiment, the present subject matter provides a process forpreparing isoxaflutole of formula (I) wherein the process comprises:admixing(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) with acetic acid, acetic anhydride, and hydrogenperoxide in the presence of a strong acid; quenching the reactionmixture; isolating the compound of formula (I); and optionally purifyingthe obtained compound of formula (I).

The present process is advantageous in that it avoids the need for usinghazardous and expensive oxidizing reagents. In addition, the process ishighly efficient, providing a short reaction time. The present processalso avoids the need for using a solvent such as dicloromethane, whichis not particularly desirable for industrial implementation due to thehazards associated with such solvent.

In particular, the use of hydrogen peroxide in the present processesreduces the cost of production, simplifies work-up, and minimizes anyeffluent disposal problems. Further, the present process achieves highyields compared to the methods known in the prior art.

Advantageously, the addition of a strong acid catalyst makes it possibleto considerably reduce reaction times while maintaining a high degree ofselectivity of oxidation of the compound of formula (II).

Advantageously, the use of acetic acid, hydrogen peroxide and optionallyacetic anhydride in the presence of a strong acid does not require theuse of any additional organic solvents for the reaction, simplifying theentire process and rendering it economically advantageous.

In one embodiment, the strong acid is selected from the group consistingof sulfuric acid, methanesulfonic acid, benzene sulfonic acid andp-toluenesulfonic acid, hydrochloric acid, nitric acid and a combinationthereof. Other strong acids typically used in oxidation reactions mayfurther be useful in the embodied processes.

In a specific embodiment the strong acid is sulfuric acid.

In an embodiment of the present processes, the molar ratio between thestrong acid and the compound of formula (II) is from about 1:1 to about1:100. In another embodiment, the molar ratio between the strong acidand the compound of formula (II) is from about 1:1 to about 1:50. In yetanother embodiment, the molar ratio between the strong acid and thecompound of formula (II) is from about 1:1 to about 1:10. In a specificembodiment, the molar ratio between the strong acid and compound offormula (II) is about 1:3.5.

In another specific embodiment the molar ratio between the strong acidand compound of formula (II) is about 1:2.2. In yet another specificembodiment the molar ratio between the strong acid and compound offormula (II) is about 1:1.1.

In one embodiment of the present processes, the molar ratio between thesulfuric acid and the compound of formula (II) is from about 1:1 toabout 1:100. In another embodiment, the molar ratio between the sulfuricacid and the compound of formula (II) is from about 1:1 to about 1:50.In yet another embodiment, the molar ratio between the sulfuric acid andthe compound of formula (II) is from about 1:1 to about 1:10. In aspecific embodiment, the molar ratio between the sulfuric acid andcompound of formula (II) is about 1:3.5. In another specific embodimentthe molar ratio between the sulfuric acid and compound of formula (II)is about 1:2.2.

In another embodiment of the present processes, the molar ratio betweenthe hydrogen peroxide and the compound of formula (II) is from about10:1 to about 1:1. In yet another embodiment, the molar ratio betweenthe hydrogen peroxide and the compound of formula (II) is from about 6:1to about 1:1. In a specific embodiment, the molar ratio between thehydrogen peroxide and the compound of formula (II) is about 5.5:1.

In a further embodiment of the present processes, the molar ratiobetween the acetic anhydride and the compound of formula (II) is fromabout 10:1 to about 1:1. In yet another embodiment, the molar ratiobetween the acetic anhydride and the compound of formula (II) is fromabout 5:1 to about 1:1. In a specific embodiment, the molar ratiobetween the acetic anhydride and the compound of formula (II) is 3:1.

In a further, optional, embodiment of the present processes, thereaction may be carried out in an organic solvent selected from thegroup consisting of monochlorobenzene, polychlorobenzene, toluene,xylene, ethyl acetate, butyl acetate, acetonitrile, N-methylpyrrolidone(NMP) and dimethylacetamide (N,N-DMA), acetone, methanol, ethanol, and acombination thereof. In yet another embodiment, the reaction is carriedout without using an organic solvent.

In one embodiment, the oxidation is conducted at a temperature fromabout 25° C. to about 100° C., more preferably from about 55° C. toabout 65° C.

In another embodiment, the hydrogen peroxide is added gradually to thereaction mixture over time. In a specific embodiment, the hydrogenperoxide is added dropwise to the reaction mixture of the(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) with acetic acid, acetic anhydride, and a strong acidover a period of about 1 hour.

In yet another specific embodiment, the hydrogen peroxide is addeddropwise to the reaction mixture of the(5-cyclopropyl-4-isoxazolyl)[2-(methylthio)-4-(trifluoromethyl)phenyl]-methanoneof formula (II) with acetic acid, acetic anhydride, and a strong acidover a period of about 0.5 hour.

In this regard, the hydrogen peroxide used in the present processes maybe in the form of aqueous solutions. For example, the usual commercialsolutions may be used, with a concentration ranging from 30 to 70% byweight. In a specific embodiment, the hydrogen peroxide is used in aconcentration of 30% by weight.

In this regard, any excess amounts of the peroxide present may bedecomposed by quenching the reaction mixture with a quenching agentselected from the group consisting of sodium metabisulfite, sodiumsulfite, sodium bisulfate, and sodium thiosulfate. Preferably, thequenching agent is a solution of sodium sulfite.

The progress of the reaction can be monitored using any suitable method,which can include, for example, chromatographic methods such as, e.g.,high performance liquid chromatography (HPLC), thin layer chromatography(TLC), and the like.

In yet another embodiment, the compound of formula (I) can be isolatedfrom the reaction mixture by any conventional techniques well-known inthe art. Such isolation techniques can be selected, without limitation,from the group consisting of concentration, extraction, precipitation,cooling, filtration, crystallization, centrifugation, and a combinationthereof, followed by drying.

In yet another embodiment, the compound of formula (I) can be optionallypurified by any conventional techniques well-known in the art. Suchpurification techniques can be selected, without limitation, from thegroup consisting of precipitation, crystallization, slurrying, washingin a suitable solvent, filtration through a packed-bed column,dissolution in an appropriate solvent, re-precipitation by addition of asecond solvent in which the compound is insoluble, and a combinationthereof.

The following examples illustrate the practice of the present subjectmatter in some of its embodiments, but should not be construed aslimiting the scope of the present subject matter. Other embodiments willbe apparent to one skilled in the art from consideration of thespecification and examples. It is intended that the specification,including the examples, is considered exemplary only without limitingthe scope and spirit of the present subject matter.

EXAMPLE 1 Analytical Method

HPLC analysis was carried out in accordance with the following methodand conditions:

-   Column: Agilent XDB C18 (4.6×150 mm, 5.0 μm)-   Temperature: 25° C.-   Mobile phase:

Time Acetonitrile 0.1% Formic acid  0 min 30% 70% 25 min 75% 25%

-   Flow rate: 1.0 ml/min-   Wavelength: 254 nm

HPLC Instrument Details:

Instrument Company Model LC-pump Agilent GI311A LC-degasser AgilentG1322A LC-ALS Agilent G1329A LC-TCC Agilent G1316A

EXAMPLE I

A typical experimental procedure is described as follows: the compoundof formula II (42 g, 128 mmoles) was added to acetic acid (80 g) andthen acetic anhydride (38 g, 370 mmoles) and sulfuric acid (3.7 g, 37.7mmoles, 0.59 eq) were added. The mixture was heated to 55-60° C., thenan aqueous hydrogen peroxide solution (80 g of 30% hydrogen peroxide)was added dropwise over 1 hr, while maintaining the reaction temperaturein the range of 55-65° C. The reaction mixture was stirred at 55-60° C.for 3-4 hr. Then, the reaction mixture was cooled to 40° C. and wasconcentrated under reduced pressure. Water (60 g) was added, stirringwas continued for 30 min, and the precipitate was filtered off. Ethanol(60 g) was added and the mixture was heated to reflux for 1.5 hr, andthen cooled to 0° C. for 0.5 hr. The precipitate was filtered off anddried in vacuum at 40-50° C. Isoxaflutole was obtained in a 65.9% yield.The reaction was also conducted in the absence of sulfuric acid(referred herein as “blank”). The solutions were analyzed by HPLC andthe percentage of the isoxaflutole and the sulfoxide intermediate Hawere monitored during reaction time (Table I).

TABLE I 0.59 eq. H₂SO₄ blank Time (IIa) IXF (IIa) IXF 0.5 hr 5.26%81.05% 46.35% 31.15% 1.0 hr 2.50% 82.69% 38.00% 38.89% 1.5 hr 30.45%49.87% 2.0 hr 23.80% 63.23% 2.5 hr 14.52% 65.57% 3.0 hr 9.80% 70.89% 3.5h  5.82% 77.50% % represents the HPLC area percent.

EXAMPLE II

A solution of acetic acid (90 gr) and the compound of formula (II) (27.3gr, 83.5 mmol) was mixed with 38 gr acetic anhydride (371 mmol) and3.7gr sulfuric acid (37.7 mmol, 0.9 eq). The solution was heated to55-60° C. 50.0gr of 30% hydrogen peroxide aqueous solution (441 mmol)was added dropwise through 0.5 h at 60-70° C. The reaction mixture wasstirred at 65-70° C. for 1.5hr, then 150gr water were added dropwisethrough 0.5hr at 65-70° C. and the mixture was stirred at 65-70° C. for0.5 hr, then cooled to ambient temperature and the precipitate wasfiltered off, washed by 150gr water and dried in vacuum at 50° C.24.15gr crude product was obtained as an off-white powder. The reactionsolution was analyzed by HPLC.

The same procedure described in example 2 was carried out without astrong acid (referred herein as “blank”) and with H₂SO₄ (0.9 eq and 0.09eq), p-toluene sulfonic acid (0.9 eq), methane sulfonic acid (0.9 eq) orbenzene sulfonic acid (0.9 eq).

The results are summarized in Table II.

TABLE II 0.9 eq. 0.9 eq. 0.9 eq. 0.9 eq 0.09 eq. p-toluene methanebenzene Time Blank H₂SO₄ H₂SO₄ sulfonic acid sulfonic acid sulfonic acid(h) (IIa) % IXF % (IIa) % IXF % (IIa) % IXF % (IIa) % IXF % (IIa) % IXF% (IIa) % IXF % 0.5 33.80 50.49 0.08 87.86 23.4 53.19 0.22 88.05 0.1585.24 0.28 71.35 1.0 19.72 65.54 0.05 89.68 1.54 83.37 0.06 89.82 0.0387.01 0.03 89.40 1.5 9.01 76.78 0.12 86.51 0.03 90.29 2.0 3.65 81.230.01 87.15 2.5 0.97 85.82 3.0 0.18 89.68 Values in the table representthe HPLC area percent (%).

EXAMPLE III

3.7gr sulfuric acid (36.4mmol) was added to 120 g of acetic acidsolution containing a compound of formula II (23.6gr, 72.1 mmol) and thereaction mixture was heated to 70° C. 30.0gr of hydrogen peroxidesolution (35%) was added dropwise through 2.5hr at the temperature rangeof 65-75° C. The mixture was stirred at 70° C. for 2hr, and then cooledto ambient temperature. The results are summarized in Table III.

TABLE III 1.0 eq H₂SO₄ Time (h) (IIa) % IXF % 1.0 0.02% 85.2

-   -   Values in the table represent the HPLC area percent

As can be seen from the results on tables I, II and III, the reaction ismuch faster when adding H₂SO₄, p-toluene sulfonic acid, methane sulfonicacid or benzene sulfonic acid compared to the reaction without a strongacid (the sample referred herein as “blank”). After 0.5h reaction thepercentage of the product isoxaflutole when adding strong acid such assulfuric acid (0.9 eq) is much higher (87.86%) compared to the blankexample (50.49%). In addition, the percentage of the intermediate Ha islower after 0.5h when using the strong acids compare to the “blank”example.

The results show higher efficiency of the reaction when adding strongacid.

While the present subject matter has been shown and described withreference to preferred embodiments thereof, it will be understood bythose skilled in the art that many alternatives, modifications andvariations may be made thereto without departing from the spirit andscope thereof. Accordingly, it is intended to embrace all suchalternatives, modifications, and variations that fall within the spiritand broad scope of the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference.

What is claimed is:
 1. A process for preparing isoxaflutole of formula(I)

wherein the process comprises: admixing the compound of formula (II)

with acetic acid and hydrogen peroxide in the presence of a strong acid.2. The process of claim 1, further comprising quenching the reactionmixture; isolating the compound of formula (I); and optionally purifyingthe obtained compound of formula (I).
 3. The process of claim 1, whereinthe molar ratio between the hydrogen peroxide and the compound offormula (II) is from about 10:1 to about 1:1.
 4. The process of claim 3,wherein the molar ratio between the hydrogen peroxide and the compoundof formula (II) is about 5.5:1.
 5. The process of claim 1, wherein theprocess is carried out in an organic solvent selected frommonochlorobenzene, polychlorobenzene, toluene, xylene, ethyl acetate,butyl acetate, acetonitrile, N-methylpyrrolidone (NMP) anddimethylacetamide (N,N-DMA), acetone, methanol, ethanol, or acombination thereof.
 6. The process of claim 1, wherein said strong acidis selected from sulfuric acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, hydrochloric acid, nitric acid or acombination thereof.
 7. The process of claim 6, wherein the molar ratiobetween the strong acid and the compound of formula (II) is from about1:1 to about 1:100.
 8. The process of claim 7, wherein said strong acidis sulfuric acid.
 9. The process of claim 8, wherein the molar ratiobetween the sulfuric acid and the compound of formula (II) is about1:3.5.
 10. The process of claim 8, wherein the molar ratio between thesulfuric acid and the compound of formula (II) is about 1:2.2.
 11. Theprocess of claim 1, wherein the process is conducted at a temperatureranging from about 25° C. to about 100° C.
 12. The process of claim 11,wherein the molar ratio between the hydrogen peroxide and the compoundof formula (II) is from about 10:1 to about 1:1.
 13. The process ofclaim 12, wherein the molar ratio between the hydrogen peroxide and thecompound of formula (II) is about 5.5:1.
 14. The process of claim 11,wherein the process is carried out in an organic solvent selected frommonochlorobenzene, polychlorobenzene, toluene, xylene, ethyl acetate,butyl acetate, acetonitrile, N-methylpyrrolidone (NMP) anddimethylacetamide (N,N-DMA), acetone, methanol, ethanol, or acombination thereof.
 15. The process of claim 11, wherein said strongacid is selected from sulfuric acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, nitricacid or a combination thereof.
 16. The process of claim 15, wherein themolar ratio between the strong acid and the compound of formula (II) isfrom about 1:1 to about 1:100.
 17. The process of claim 16, wherein saidstrong acid is sulfuric acid.
 18. The process of claim 17, wherein themolar ratio between the sulfuric acid and the compound of formula (II)is about 1:2.2.
 19. The process of claim 18, wherein the molar ratiobetween the hydrogen peroxide and the compound of formula (II) is fromabout 10:1 to about 1:1.
 20. The process of claim 19, wherein the molarratio between the hydrogen peroxide and the compound of formula (II) isabout 5.5:1.